The overall goal of this project is to define the molecular events involved in the transformation of low grade lymphomas to more aggressive forms. We have chosen follicular lymphoma as our primary model because it is a homogeneous disease, characterized primarily by a single molecular lesion (bcl-2 translocation) and because over 70% of these low grade lymphomas will evolve into a histologically distinct high grade lymphoma. For the past few years we have been analyzing the role of known oncogenes and tumor suppressor genes in a large series of progressed follicular lymphomas, using a combination of molecular genetic and immunohistochemical techniques. We have completed studies on the involvement of the myc gene and have found acquired, progression related structural changes in this gene in approximately 10% of progressed lymphomas. We have also found that approximately 30% of transformed follicular lymphomas harbor acquired p53 mutations, not present in a significant percentage of tumor cells in the antecedent low grade lymphoma. This suggests that a substantial proportion of follicular lymphomas undergo histologic progression via a pathway that involves mutation of the p53 gene. We are also currently investigating the role of MDM-2 and p21, additional genes involved in the p53 pathway. Other genes under investigation include BCL-6, Rb, PCNA and p16. We have started a search for new progression related genes through the use of differential expression displays of pre- and post- transformation lymphomas from individual patients through the use of representational difference analysis, and through the use of comparative genomic hybridization.